Clinicopathological Significance, Related Molecular Changes and Tumor Immune Response Analysis of the Abnormal SWI/SNF Complex Subunit PBRM1 in Gastric Adenocarcinoma

Abstract

Background: PBRM1 gene abnormalities were recently found to play a role in tumor development and tumor immune activity. This article will explore the clinicopathological and molecular changes and tumor immune activity of the abnormal SWI/SNF complex subunit PBRM1 in gastric adenocarcinoma (GAC) and its significance. Methods: The cBioPortal, LinkedOmics and TISIDB datasets were used to analyze the abnormality of the PBRM1 gene in GAC and its relationship with prognosis, related molecular changes and tumor-infiltrating lymphocytes (TILs). In addition, 198 GAC cases were collected to further study the relationship between the loss/attenuation of PBRM1 expression and clinicopathology, prognosis, microsatellite stability, PD-L1 expression and TIL in GAC. DNA whole-exome sequencing was performed on 7 cases of gastric cancer with loss of PBRM1 expression. Results: The cBioPortal data showed that PBRM1 deletion/mutation accounted for 7.32% of GAC and was significantly associated with several molecular changes, such as molecular subtypes of GAC. The LinkedOmics dataset showed that PBRM1 mutation and its promoter DNA methylation showed lower PBRM1 mRNA expression, and PBRM1 mutation cases showed significantly higher mRNA expression of PD-L1 (CD274). TISIDB data showed that PBRM1 abnormalities were significantly positively associated with multiple TILs. In our group of 198 cases, the loss/attenuation of PBRM1 expression was significantly positively correlated with intra-tumoral tumor infiltrating lymphocytes (iTILs) and deficient MMR and PD-L1 expression. Kaplan-Meier survival analysis showed that the overall survival of GAC patients with loss/attenuation of PBRM1 expression was significantly better (p = 0.023). iTIL was an independent prognostic factor of GAC. Loss of PBRM1 expression often co-occurs with mutations in other SWI/SNF complex subunit genes, and there are some repetitive KEGG signaling changes. Conclusion: Abnormality of the PBRM1 gene may be related to the occurrence of some GACs and can affect tumor immune activity, thereby affecting clinicopathology and prognosis. It may be a potentially effective predictive marker for immunotherapy and a novel therapeutic approach associated with synthetic lethality.

Keywords: PBRM1; PD-L1; gastric adenocarcinoma (GAC); microsatellite stability; prognosis; tumor-infiltrating lymphocytes (TIL).

FIGURE 1

PBRM1 deletion/mutation in GAC and its relationship with various molecular alterations in cBioPortal data (CIN, chromosomal instability; EBV, Epstein-Barr virus type; GS, genome stability; MSI, microsatellite instability; MSH-H, microsatellite instability-High; MSH-L, microsatellite instability-Low; MSS, microsatellite stability; 0 = No, 1 = Yes).

FIGURE 2

The LinkedOmics dataset shows that PBRM1 mRNA expression is significantly lower in PBRM1 mutant cases (Wilcoxon Test) (A) and significantly negatively correlated with PBRM1 promoter DNA methylation (Pearson Correlation test) (B) in GAC.

FIGURE 3

The relationship between PD-L1 (CD274) (A) and CTLA4 (B) mRNA expression and PBRM1 mutation in GAC in the LinkedOmics dataset (Wilcoxon Test).

FIGURE 4

The prognosis of GAC patients with PBRM1 abnormalities. In the 354 cases of the LinkedOmics dataset, the prognosis of GAC patients with PBRM1 mutation is relatively better than that of PBRM1 wild-type patients (Cox Regression Test, HR = −0.5009, p = 0.2311) (A), and the overall survival of PBRM1 expression loss/attenuation is significantly better in the 198 cases of our group (log-rank test, Chi square value = 5.159, p = 0.023) (B).

FIGURE 5

The TISIDB database shows that PBRM1 mutation is significantly associated with activated CD4 (A) and activated CD8 T cells (B) (Wilcoxon Test).

FIGURE 6

PBRM1, MMR, and PD-L1 expression and iTIL of GAC in our group. PBRM1 (A), MLH1 (C), MSH2 (E) and PMS2 (G) nuclear expression was lost [(B,D,F,H) showed that the expression of the 4 markers were retained, respectively)]; PD-L1 (I) cytoplasmic expression was expressed [(J) showed negative expression of PD-L1]. Using the EnVision method. Intra-tumoral TILs were ≥5 lymphocytes per high-power field (K) [(L) showed no iTILs] (HE staining). ×200 magnification.

FIGURE 7

KEGG signaling pathways (A) and biological processes (B) mainly enriched in GACs with PBRM1 expression loss.